1. Field of the Invention
The most important medicament for the treatment of specific tumour forms, especially hormone-dependent breast tumours, is the antioestrogen tamoxifen (1-(p-3-dimethylaminoethoxyphenyl)-trans-1,2-diphenylbut-1-ene).
2. Background Art
Tamoxifen is available commercially in various oral formulations under various Trade Marks, in particular Novaldex.RTM.. Tamoxifen is administered perorally in the long-term treatment of tumours at from 10 to 40 mg per single dose. The daily dose is from 20 to 40 mg. In the case of long-term therapy, however, tamoxifen exhibits serious undesired side-effects, for example, the paradoxical stimulation of the ovaries, which presents a limiting factor in its long-term use. During passage through the liver after absorption from the gastrointestinal tract, the active metabolite 4-hydroxytamoxifen is produced from the tamoxifen and, on a molecular basis, is more active than tamoxifen by a factor of approximately 100. That value is based on the publication by Katzenellenbogen et al. (Bioactivities, oestrogen receptor interactions, and plasminogen activator-inducing activities of Tamoxifen and Hydroxytamoxifen Isomers in MCF-7 Human Breast Cancer Assays) in Cancer Research, 44 (1984) 112-119, on MCF-7 cell lines. The substance isomeric to 4-hydroxytamoxifen, 3-hydroxytamoxifen (Droloxifen), likewise binds very much more strongly to oestrogen receptors in vitro, that is by a factor of from 20 to 60, than tamoxifen itself. As in the case of 4-hydroxytamoxifen, the oestrogenically active component is less than in tamoxifen, whereas the antioestrogenic activity is in each case higher. The oestrogenic component of both tamoxifen and its hydroxy derivatives is associated with the stereoisomeric E-form, whilst the antioestrogenic component results from the Z-form. The hydroxy derivatives of tamoxifen undergo extensive metabolisation in the liver, at any rate after oral administration, as described, for example, by DE-C-2 807 599. The substances are very rapidly conjugated and thereby inactivated (Rochefort et al, (Cellular and molecular mechanism of action of antioestrogens) in J. Steroid Biochem., 19 (1983) 69-74).
On account of the high receptor affinity of hydroxytamoxifen derivatives, their therapeutic use would be desirable but, using the peroral route, it is very severely restricted because of their rapid inactivation in the liver. For that reason EP-B-0 169 214 and EP-B-0 151 326 describe the topical administration of 4-hydroxytamoxifen in an aqueous/alcoholic gel. The gel is provided for the topical application of 4-hydroxytamoxifen. In Cancer Research, 46 (1986) 1521-1525, Mauvais-Jarvis et al describe the topical administration of an alcoholic solution to 12 female patients. In that study, the distribution of radioactive 4-hydroxytamoxifen in breast tissue was examined. The authors discovered that the percutaneous topical application of 4-hydroxytamoxifen resulted first of all in a high retention of the active ingredient in the oestrogen receptor-containing breast tissue and transition to the plasma compartment was delayed for a very prolonged period. Only approximately 0.5% of the dose applied was found unchanged in the plasma.
The provision of a systemic method of administration is desirable, however, in the case of, for example, metastasising tumours, where 4-hydroxytamoxifen cannot be administered topically in every case. The percutaneous form of medicament described in the above-mentioned EP-B publications, that is the aqueous/alcoholic gel, is disadvantageous. Such gels cannot be applied per se to defined cutaneous areas, and cannot be protected from external influences, such as being washed off, or rubbed off by clothing, during the period of action. The delivery of active ingredient from such gels is accordingly very variable and unreliable.
The problem underlying the invention is to make available a systemic method of administration for tamoxifen derivatives.